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Abstract:

Novel transdermal preparations combining a non-steroidal
anti-inflammatory drug (NSAID) selected from groups such as oxicams (for
example, meloxicam), propionic acids (for example, ketoprofen) and
anthranilic acids (for example, tolfenamic acid), are disclosed. Methods
for using and administering such preparation in the treatment of
inflammatory conditions in bovines are also disclosed.

34. A method of treating inflammatory conditions, comprising
administering an effective amount of a veterinary pour-on preparation of
claims 25 to 33 to an animal in need thereof.

35. The method according to claim 34 wherein the animal is a bovine
animal.

36. A method of administering the veterinary pour-on preparation of claim
25 comprising a) incorporating said veterinary pour-on preparation into a
press-in bottle application device, and b) administering an effective
amount of said veterinary pour-on preparation to an animal in need
thereof.

37. The method according to claim 36 wherein the animal is a bovine
animal.

Description:

FIELD OF THE INVENTION

[0001] The present invention relates to compositions and methods for the
treatment of inflammation in animals. More particularly, the invention
relates to transdermal administration of non-steroidal anti-inflammatory
compounds (NSAID) to non-human animals.

BACKGROUND OF THE INVENTION

[0002] All patents, applications, publications, test methods, and other
materials cited herein are incorporated by reference.

[0003] Inflammation is a process that occurs in response to injury or
other abnormal stimulation by physical, chemical, or biological agents,
with the purpose of helping to overcome the abnormal stimulus.
Inflammation involves local tissue reactions and morphologic changes,
destruction or removal of injurious material, and the initiation of
repair and/or healing. Cardinal signs of active inflammation include
redness, heat, swelling, pain, and reduction or loss of function; these
signs can present locally and/or systemically.

[0004] While the purpose of an inflammatory response is to help the host
overcome an abnormal stimulus, inflammatory episodes can have deleterious
effects. In the short-term, febrile or painful animals may have reduced
feed and water intake, which can create the risk of developing problems
related to a negative energy balance or dehydration. Furthermore, some
inflammatory episodes can leave long-lasting residual damage, scarring,
and reduced functionality.

[0005] For example, bovine respiratory disease (BRD) occurs in both dairy
and beef cattle and is one of the leading causes of economic loss to the
cattle industry throughout the world. Economic losses are attributable to
excessive mortality, treatment and prevention costs, and decreased
productivity--dairy cattle with clinical or sub-clinical BRD do not gain
weight or produce milk as well as healthy animals, and beef cattle with
BRD gain less weight, have reduced feed efficiency and often produce a
lower grade carcass at slaughter. A direct correlation between pulmonary
lesions observed at slaughter and reduced weight gains has been
established in cattle with sub-clinical BRD infections. The etiologic
agents of BRD include bacterial organisms such as Mannheimia haemolytica,
Pasteurella multocida and Histophilus somni. However, in BRD infections,
the pulmonary damage that results in death or morbidity is often due to
an excessive host inflammatory response to the invading pathogens. In the
short term, febrile, painful animals eat and drink less. Furthermore,
long-term damage to host tissues occurs, resulting in long-term declines
in productivity even after BRD infection has resolved.

[0006] Bovine mastitis is considered to be the most costly production
disease faced by the dairy industry, costing hundreds of millions of
dollars per year. Bovine mastitis is typically caused by infectious
agents such as Staphylococcus aureus, Streptococcus species, and
Escherichia coli. In response to infection, the mammary gland undergoes
an inflammatory process, characterized by warmth, pain, redness,
swelling, and impaired function. The affected animal often develops a
fever and eats and drinks less. There is a transient decrease in milk
production during the acute inflammatory stage, and subsequent milk yield
for the remainder of the lactation is reduced as a result of residual
inflammatory damage.

[0007] In addition to cattle, other species are similarly susceptible to
short-term and long-term effects of inflammatory episodes induced by a
variety of causes. Regardless of species or causative agent, the damage
brought about by inflammation evolves as neutrophils and other
inflammatory cells destroy affected tissues. As cell membranes are
damaged, arachidonic acid is released. Arachidonic acid is the substrate
for the formation of various prostaglandins and other eicosanoids. The
release of these biologically active substances is critical to driving
the inflammatory response that results in additional pain, inflammatory
damage and lesions. Non-steroidal anti-inflammatory drugs (NSAIDs)
effectively modulate inflammation by disrupting the arachidonic acid
cascade.

[0008] Use of NSAIDs is a cornerstone of management of pain and
inflammatory processes in human and veterinary medicine. Regardless of
the species or organ system affected or the cause, pharmacologic
modulation of inflammation offers important quality of life benefits to
painful or febrile animals, allowing the affected animal to eat and drink
and thus increase the potential for recovery. Furthermore, use of NSAIDs
helps to reduce excessive damage that results in long-term reduction of
functionality, thus bringing economic benefits to livestock producers.

[0009] Based on structure, most commercially available veterinary NSAIDs
can be divided into 2 broad classes--carboxylic acid and enolic acid
derivatives. These classes can be further divided into groups based on
similar molecular structures. NSAIDs within a group--those that share
similar molecular will tend to have similar characteristics and
tolerability. The main groups of enolic acids are the pyrazolones
(phenylbutazone, oxyphenbutazone, and ramifenazone) and the oxicams
(meloxicam, piroxicam, and tenoxicam). Carboxylic acid groups include the
salicylates (aspirin), propionic acids (ibuprofen, naproxen, carprofen,
ketoprofen, and vedaprofen), anthranilic acids (tolfenamic and
meclofenamic acids), phenylacetic acids (acetaminophen), aminonicotinic
acids (flunixin), and indolines (indomethacin).

[0010] Currently there are several NSAIDs commercially available for
cattle and licensed in several countries i.e. flunixin megiumine
(Finadyne® Injection, Schering-Plough Animal Health), ketoprofen
(Ketofen®10%, Merial), meloxicam (Metacam®, Boehringer Ingelheim)
and tolfenamic acid (Tolfine®, Vetoquinol). All products are licensed
for being administered parenterally.

[0011] Conventionally, NSAID products are administered to animals
parenterally by injection. Flunixin meglumine is e.g. currently
formulated for intravenous or intramuscular injection, meloxicam for
intravenous or subcutaneous injection, and ketoprofen and tolfenamic acid
for intravenous or intramuscular injection. This means the administration
is performed by injection, using a syringe and needle.

[0012] In order to properly inject a drug to a bovine animal, like cattle,
it is necessary to restrain the animal properly in order to avoid any
injury to the animal and the farmer or veterinarian. Furthermore
injection through the skin may lead to injection site reaction, i.e.
local inflammation reactions in the tissue circumventing the injection
site. Such tissue reaction might persist until the slaughter of the
animal and under certain circumstances will be still present in the meat
for human consumption. In addition, any injection to big herds of cattle
animals under practice conditions bears the risk, that infections are
transferred from one animal to the other by the needle used.
Consequently, there is a need for alternative administration methods of
NSAID drugs that avoid these drawbacks and are safe to use, and avoid
such risk, injury and injection site reactions.

[0013] Thus, there is a need for an improved formulation and method of
administration, such as a formulation for transdermal drug delivery,
which addresses these problems. One difficulty faced, however, when
attempting to arrive at a transdermal formulation is the fact that the
skin has been described as a "black box" with regard to drug delivery.
This is due to the lack of knowledge in the mechanisms of drug
penetration through the epidermis and partitioning into the underlying
layers. Thus far, the boundaries for such properties have not been
defined; making it very difficult to predict what compounds can be
delivered transdermally.

[0014] Transdermal systems effective for delivering one compound are
almost always ineffective with other compounds. Also, systems and devices
that work in one species are usually ineffective in other species.
Furthermore, due to the presence of the stratum corneum barrier, the mass
transfer through the skin is usually too slow for rapid, massive systemic
absorption. This explains why very few, if not any, of the commercially
available transdermal products for human use are designed for immediate
drug delivery. Transdermal drugs that work in humans are not always
suitable for fur bearing animals, especially for bovine animals.

[0015] Accordingly, there is a need for stable, transdermal liquid
preparation that offers a way for handlers to safely and conveniently
administer NSAID compounds to animals in need thereof to ameliorate pain
and inflammation, while minimizing the pain and stress to the animal
associated with treatment and the potential for injection site tissue
damage.

SUMMARY OF THE INVENTION

[0016] The present invention fulfills this need by providing improved
preparations and methods for the delivery of NSAID compounds selected
from the group consisting of oxicams, propionic acids, and anthranilic
acids, or pharmaceutically acceptable salts thereof to animals,
especially bovine animals.

[0017] In one embodiment the NSAID compound of the oxicams group is
meloxicam, of the propionic acids group is ketoprofen and of the
anthranilic acids group is tolfenamic acid.

[0018] Accordingly, there are disclosed pharmaceutically acceptable
preparations for transdermal administration to animals and methods for
the use thereof. Such preparations comprise one or more of a NSAID
compound selected from the oxicams group, the propionic acid group and
the anthranilic acid group or pharmaceutically acceptable salts thereof,
a pharmaceutically acceptable carrier system comprising at least one
solvent, and at least one dermal penetration enhancer. In optional
aspects of the invention, the transdermal liquid preparations can include
a stabilizing or viscosity lowering agent, such as water, ethanol,
isopropanol, propylene glycol, dimethylisosorbide, triacetin, or
glycerol.

[0019] One preferred aspect of the invention includes a transdermal liquid
preparation containing: [0020] a) a NSAID compound selected from one of
the following groups: oxicams, propionic acids and anthranilic acids or
pharmaceutically acceptable salts thereof; [0021] b) at least one dermal
penetration enhancer; and [0022] c) at least one solvent.

[0023] Within the first and second aspect of the invention, the dermal
penetration enhancer can be present in an amount from about 2% to about
90% of the transdermal liquid preparation. Preferred dermal penetration
enhancers include menthol, xylene, D-limonene, isopropyl myristate,
propylene glycol dicaprylate/dicaprate, decanoic acid, decyl alcohol,
oleic acid, or mixtures thereof.

[0024] The amount of the non steroidal anti-inflammatory (NSAID) compound
selected from oxicams, propionic acids and anthranilic acids included in
the transdermal liquid preparations described herein can be present in an
amount from about 0.5 to about 40% by wt., while the amount of the
solvent can broadly be from about 10 to about 90% by wt. Preferred
solvents useful in the present invention include pyrrolidone solvents
such as 2-pyrrolidone or N-methyl-2-pyrrolidone, ethyl lactate, and
glycol ethers such as ethylene glycol monoethyl ether, diethylene glycol
monoethyl ether, dipropylene glycol monoethyl ether, ethanol, isopropyl
alcohol, and benzyl alcohol.

[0025] In another aspect of the invention, there are provided methods of
treating pain and inflammatory conditions. Some of these methods include
administering an effective amount of a transdermal preparation as
described above to an animal, like a mammal such as a bovine animal (e.g.
cow) in need thereof.

[0026] The present preparation can also optionally include other NSAIDs
besides oxicams, propionic acids and anthranilic acids, as well as other
active pharmaceutical ingredients such as anti-microbials, hormones for
reproduction, growth enhancement, or other physiologic intervention,
anxiolytic compounds, antihistamines, immune stimulants, vaccines and the
like, for example.

[0027] In another aspect of the invention, there are provided methods of
administering the transdermal NSAID liquid preparation incorporating the
transdermal liquid preparation into a press-in bottle application device,
and administering an effective amount of the transdermal liquid
preparation to an animal in need thereof.

[0028] With the foregoing and other objects, advantages and features of
the invention that will become apparent hereinafter, the nature of the
invention may be more clearly understood by reference to the following
detailed description of the invention and the appended claims.

BRIEF DESCRIPTION OF THE FIGURES

[0029] FIG. 1 is a graph showing the results of one of the tests carried
out in the experiment described in Example 2, wherein the mean plasma
concentration of meloxicam was measured following a single transdermal or
injectable dose in cattle.

[0030] FIG. 2 is a graph showing the results of one of the tests carried
out in the experiment described in Example 2, wherein the mean plasma
concentration of ketoprofen was measured following a single transdermal
or injectable dose in cattle.

[0031]FIG. 3 is a graph showing the results of one of the tests carried
out in the experiment described in Example 2, wherein the mean plasma
concentration of tolfenamic acid was measured following a single
transdermal or injectable dose in cattle.

DETAILED DESCRIPTION OF THE INVENTION

[0032] It has been found that effective concentrations of a NSAID compound
selected from oxicams, propionic acids, or anthranilic acids or
pharmaceutically acceptable salts thereof in the systemic circulation for
the purpose of providing systemic anti-inflammatory activity can be
achieved by the transdermal route of administration. This can encompass
various types of delivery including pour-on, spot-on, spray, dip, wipe,
etc.

[0033] The present invention relates to an NSAID product for providing
systemic anti-inflammatory (including anti-pyrexia and analgesia)
activity for animals, especially bovine mammals such as cows. The present
invention demonstrates that, through improved compositions and methods of
delivery a NSAID compound selected from the following groups: oxicams
(for example, meloxicam), propionic acids (for example, ketoprofen), or
anthranilic acids (for example, tolfenamic acid) can effectively diffuse
through the skin and further partition into the underlying layers for
rapid absorption. It was discovered that the pharmacokinetic parameters
of the present invention are comparable to those obtained by the
counterpart injectable formulations. The pharmacokinetic data shows high
bioavailability and efficiency of skin barrier penetration, as well as
tissue partitioning from the current formulations.

[0034] As used herein, the following terms, unless otherwise indicated,
shall be understood to have the following meanings:

[0035] Non-steroidal anti-inflammatory drugs, usually abbreviated to
NSAIDs, are drugs with analgesic, antipyretic and, in higher doses,
anti-inflammatory effects--they reduce pain, fever and inflammation. The
term "non-steroidal" is used to distinguish these drugs from steroids,
which (among a broad range of other effects) have a similar
eicosanoid-depressing, anti-inflammatory action. NSAIDs can be classified
based on their chemical structure. NSAIDs within a group--those that
share similar molecular structures--will tend to have similar
characteristics and tolerability.

[0037] Anthranilic acids (N-Arylanthranilic acids) are based on the
molecule fenamic acid, which is formed by two carbon rings attached in
the middle with one nitrogen atom, and with one carboxyl group (COOH) on
one of the rings. Anthranilic acids are e.g. mefenamic acid, tolfenamic
acid, flufenamic acid, and meclofenamic acid. Tolfenamic acid is
2-[(3-chloro-2-methylphenyl)amino]benzoic acid). (CAS13710-19-5).

[0039] "transdermal application" and/or "transdermal liquid preparation"
is intended to encompass all such methods known for allowing a
pharmaceutically active ingredient to be delivered at least partially
through the skin, usually by applying the composition containing the
active ingredient and formulation excipients externally to the surface,
i.e. skin, fur, etc. of an animal and allowing sufficient time for
absorption through the dermal layers of the animal being treated. Methods
of administration include pour-on, spot-on, spray, dip, wipe, or other
methods apparent to those skilled in the art;

[0040] "pour-on" is intended to encompass routes of administration in
which an effective amount of a suitable pharmaceutically active
ingredient is externally applied to a localized region, allowing for
diffusion of an effective amount of the pharmaceutically active
ingredient to the affected area(s) or systemic distribution or a region
which will facilitate delivery of the pharmaceutically active ingredient
to the affected area(s) or systemic distribution;

[0041] "composition" "formulation" and/or "preparation" is intended to
encompass a product comprising the specified ingredients disclosed herein
in the specified amounts disclosed herein, as well as any product which
results, directly or indirectly, from combination of the specified
ingredients disclosed herein in the specified amounts disclosed herein;
and

[0042] "effective amount" is a dose required to alleviate a particular
symptom of an infection or disease.

[0043] In accordance with a first aspect of the invention, the transdermal
liquid preparation contains a therapeutically effective amount of a NSAID
compound selected from the following groups: oxicams (for example,
meloxicam), propionic acids (for example, ketoprofen), or anthranilic
acids (for example, tolfenamic acid) or a pharmaceutically acceptable
salt thereof, a dermal penetration enhancer, and a solvent.

[0044] In the preparations of the invention, the concentration of the
NSAID compound can be from about 0.5% to about 40% by weight of the
transdermal liquid preparation, or particularly from about 1% to about
20% by weight, or particularly with amounts being from about 2% to about
15. The NSAID compound selected from the oxicams (for example,
meloxicam), propionic acids (for example, ketoprofen), or anthranilic
acids (for example, tolfenamic acid) can be introduced into the
preparation as a pharmaceutically acceptable salt, in which case the
concentration of the salt would be adjusted in order to maintain the
preferred NSAID compound concentration.

[0045] The transdermal liquid preparation of the invention also includes a
dermal penetration enhancer. In particular embodiments of the invention,
the dermal penetration enhancer is present in amounts from about 2 to
about 90% w/v of the transdermal liquid preparation, particularly from
about 5 to about 80% w/v or particularly from about 10 to about 70% w/v.

[0047] In one embodiment the transdermal liquid preparation of the
invention includes two or more dermal penetration enhancer.

[0048] In particular embodiments of the invention, the first dermal
penetration enhancer is present in amounts from about 2 to about 30% w/v
of the transdermal liquid preparation, particularly from about 3 to about
25% w/v or particularly from about 5 to about 20% w/v.

[0050] The optional second dermal penetration enhancer is particularly
present in an amount from about 2 to about 90% w/v of the transdermal
liquid preparation, particularly from about 5 to about 80% w/v, or more
particularly from about 10 to about 70% w/v.

[0051] Non-limiting examples of a suitable optional second dermal
penetration enhancer include, but are not limited to, a second terpenoid,
saturated or unsaturated fatty acid esters or diesters of propylene
glycol or esters, diesters or triesters of glycerol, saturated or
unsaturated fatty acids, saturated or unsaturated fatty alcohols and
mixtures thereof.

[0053] In one particular preparation of the invention, the first dermal
penetration enhancer is menthol, and the optional second dermal
penetration enhancer is propylene glycol dicaprylate/dicaprate and/or
xylene and/or D-limonene and/or isopropyl myristate and/or mixtures
thereof.

[0054] In one embodiment the penetration enhancer is a combination of
propylene glycol dicaprylate/dicaprate and menthol.

[0055] In case more than one penetration enhancer is employed the ratio of
the first dermal penetration enhancer to the optional second dermal
penetration enhancer is from about 4:1 to about 1:20.

[0056] The transdermal liquid preparation of the invention also includes a
solvent. In particular formulations of the invention, the solvent is
present in an amount from about 5 to about 90% by weight of the
transdermal liquid preparation, particularly, from about 10 to about 80%
by weight.

[0058] Non-limiting examples of other solvents include, but are not
limited to, water, ethanol, isopropanol, 1,2-propanediol, glycerin,
benzyl alcohol, dimethylisosorbide, triacetin, propylene glycol, ethyl
lactate, glycol ethers such as ethylene glycol monoethyl ether,
diethylene glycol monoethyl ether (DEGMEE), or dipropylene glycol
monoethyl ether, and polyethylene glycols (PEG) having an average
molecular weight between about 200 and 1000. In particular, solvents
include isopropyl alcohol, benzyl alcohol, and PEG having an average
molecular weight between about 200 and about 1000, triacetin,
dimethylisosorbide, ethanol, and water, and combinations thereof.

[0059] The addition of one or more of additional other solvents may be
desirable to alter the viscosity of the formulation in order to provide a
product with appropriate characteristics for transdermal application.

[0060] The transdermal liquid preparation of the invention can also
optionally include a second pharmaceutically active compound, or other
therapeutic classes of drugs such as anti-microbials, anti-inflammatory
agents, oxytocin, hormones for reproduction, growth enhancement
compounds, physiologic intervention compounds, anxiolytic compounds,
antihistamines, immune stimulants, and vaccines and the like, for
example. As will be appreciated by those of ordinary skill, a wide
variety of pharmaceutically active compounds/agents can be included with
the NSAID compound based transdermal formulations described herein. The
only limitation on the type of pharmaceutical agent which can be included
is that the second agent must not significantly interact with or
significantly diminish the activity of the NSAID compound or
pharmaceutically acceptable salt being transdermally administered.

[0061] A non-limiting list of suitable pharmaceutically active compounds
include those falling in the categories of anti-inflammatory agents, such
as NSAIDs and corticosteroids, antibiotics, anti-pyretics, analgesics,
etc. and the like. In one particular aspect, the transdermal formulations
will include an antibiotic such as a fluorine-containing analog
chloramphenicol and thiamphenicol, such as florfenicol. Examples of such
compounds, and methods for their manufacture, are described and claimed
in U.S. Pat. No. 4,235,892.

[0063] Other ingredients can be added to the present composition, as
desired. Such ingredients include preservatives, chelating agents,
antioxidants, and viscosity modifying agents. Exemplary preservatives
include without limitation methyl p-hydroxybenzoate (methylparaben) and
propyl p-hydroxybenzoate (propylparaben), added in an appropriate
quantity known to one skilled in the art. Exemplary chelating agents
include without limitation edetate disodium and EDTA. Exemplary
antioxidants include without limitation butylated hydroxyanisole,
ascorbic acid, and sodium monothioglycerol, added in an appropriate
quantity known to one skilled in the art. Suitable viscosity modifying
agents include, without limitation, water, ethanol, isopropanol,
propylene glycol, dimethylisosorbide, triacetin, or glycerol, added in an
appropriate quantity known to one skilled in the art.

[0064] In order to prevent degradation of any of the active ingredients in
the formulations of the present invention, the addition of at least one
stabilizer has been found to be advantageous. In order to prevent
degradation of any of the active ingredients in the formulations of the
present invention, a pH adjusting agent has been found to be
advantageous.

[0065] The amount of the active agent(s) or any other excipients may be
varied to alter the dose volume delivered or the physical properties of
the formulation. The amount of the second pharmaceutically or
therapeutically active agent will depend on transdermal bioavailability
and pharmacologic synergy with other actives in the formulation and will
be titrated to effect.

[0066] In some particular embodiments, the transdermal preparations in
accordance with the invention have a similar plasma profile to that
observed with the commercially available injectable products for cattle
containing meloxicam, ketoprofen or tolfenamic acid as active ingredient.

[0067] It will also be appreciated that the present invention encompasses,
in one aspect, methods of treating inflammation by administering, the
preparation as described above to an animal, especially a bovine animal
by transdermal administration.

[0068] The transdermal liquid preparation according to the invention has
an unexpected high absolute systemic bioavailability. Bioavailability is
a measurement of the extent of a therapeutically active drug that reaches
the systemic circulation and is available at the site of action. It is
expressed as the letter F. Absolute bioavailability measures the
availability of the active drug in systemic circulation after
non-intravenous administration (i.e., after oral, transdermal,
subcutaneous administration).

[0069] The absolute bioavailability is the dose-corrected area under curve
(AUC) non-intravenous divided by AUC intravenous. For example, the
formula for calculating F for a drug administered by the oral route (po)
is given below.

F = [ A U C ] po * dose IV [ A U
C ] IV * dose po ##EQU00001##

[0070] In one embodiment the preparation according to the invention has an
absolute systemic bioavailability of at least 10% after transdermal
administration. In particular the preparation according to the invention
has an absolute systemic bioavailability of 10-20%. In a preferred
embodiment the absolute systemic bioavailability is higher than 20%.

[0071] The preparation can be applied in a variety of ways, such as a
pouring, spraying, or wiping on to any area of the animal's skin,
including the back, ears, or udder, preferably the back of the animal.

[0072] The present invention also includes a transdermal preparation for
the treatment of inflammatory conditions in an animal. Particularly, the
transdermal preparation comprises from about 2% to about 90% by wt of a
dermal penetration enhancer, from about 0.05% to about 40% of the NSAID
compound or a pharmaceutically acceptable salt thereof, from about 10% to
about 90% of a solvent. In addition to greater convenience and ease of
use, it is believed that a single daily administration of a transdermal
product in accordance with the present invention will promote humane
animal care by reducing the number of injections needed to treat animals
and providing rapid relief of disease symptoms. By reducing the number of
injections, manpower costs also may be significantly reduced.

[0073] In a particular method of preparing the composition of the present
invention, the vehicle(s) or a portion of the vehicle(s), are added to
the compounding vessel, followed by the remaining excipients and the
actives. The mixture is mixed until all solids are dissolved. An
additional solvent to bring the composition to final volume may be added
if needed. Additives, such as those listed above, may also be included in
the vessel and mixed into the formulation. The order of addition of the
above vehicles, excipients, solvents and additives is not critical.

[0074] The preparations may be administered once daily or divided into
multiple doses. In some circumstances, daily doses will be required to
treat the animal. The precise dose will depend on the stage and severity
of the condition being treated, and the individual characteristics of the
animal species being treated, as will be appreciated by one of ordinary
skill in the art.

[0075] The preparations of the present invention may be administered in a
press in bottle insert application device (PIBA) to an animal in need
thereof. Such a device allows a health care professional to easily
dispense liquids from stock bottles into (oral) syringes. In
administering the composition, the professional opens the bottle and
presses the plastic adapter into the opening of the bottle and then
attaches the oral syringe to the port of the adapter. Next, the
professional may withdraw the dose of medication from the bottle and
administer the dose. Then the cap can be replaced on the bottle to be
used later. Presently, animal pour-on products generally require
administering larger volumes of a composition, thus, the above-described
method of administration is not appropriate. Therefore, present pour-on
products are either administered in a dosing gun or a dosing cup. Such
methods of administration prove difficult to accurately deliver small
volumes of medication. Thus, the method of administration of the present
invention using the PIBA application system allows for more accurate and
convenient administration of the presently claimed pour-on liquid
preparation.

[0076] The preparations according to the present invention are
particularly useful for bovine animals. In this specification, bovine
animals are ruminant mammals of the genus Bos and include, but are not
limited to, cattle, steers, heifers, cows (lactating and non-lactating),
calves, bulls, and also buffalo

[0077] In addition to the treatment of BRD, the compositions of this
invention are also suitable for the treatment of other conditions
associated with inflammation such as footrot, acute mastitis, pinkeye
(infectious keratoconjunctivitis), acute pneumonia, metritis and
enteritis in bovine animals. The dosage regimen for treatment of such
diseases should be appropriate for the species and condition being
treated.

[0078] Mastitis is a complex disease that occurs in lactating females, and
is of particular economic importance in dairy cows and goats. Several
pathogenic agents may be involved, including Staphylococcus aureus,
Escherichia coli, and Streptococcus species. The acute form of mastitis
has a sudden onset, the udder is enlarged, hot to the touch and tender;
and usually the affected animal will have a fever. If not treated
promptly, the udder may be permanently damaged and milk production may be
decreased or lost.

[0079] Pinkeye is an acute infectious disease of cattle, sheep and other
animals that is characterized by inflammation of the tissues of the eye,
accompanied by nasal discharge, lacrimation and copious ocular discharge.
Affected animals may display extreme discomfort, resulting in decreased
feed intake and subsequent reduction in body weight gain and/or a drop in
milk production. In extreme cases, permanent blindness occurs. The
disease, which is caused by Moraxella bovis in cattle, is widespread,
especially among range and feedlot cattle, the cure of which is of great
economic importance to the cattle industry.

[0080] Footrot (interdigital phlegmon) is an acute infection of the
interdigital space that occurs throughout the world in both beef and
dairy cattle. Fusobacterium necrophorum is the major cause of footrot,
although other organisms, including Bacteroides melaminogenicus, can be
involved. The major symptoms include pain, severe lameness, fever,
anorexia, and reduced milk production. Currently, footrot is treated by
antibiotic therapy. Recommended therapy can involve treatment for up to
five days. The use of the preparations of the present invention would be
a useful adjunct therapy because the NSAID would reduce the inflammation
caused by footrot and make the animal feel better.

EXAMPLES

[0081] The materials and methods of the present invention are further
illustrated by the examples which follow. These examples are offered to
illustrate, but not to limit, the claimed invention.

[0083] In order to prepare the compositions of the Example, the vehicle(s)
or a portion of the vehicle(s), are added to the compounding vessel,
followed by the remaining excipients and the actives. The combination is
mixed until all solids are dissolved. Although not included herein,
additives, such as those mentioned in the detailed description, are also
included in the vessel and mixed into the formulation. The order of
addition was not critical.

Example 2

Experiments to Measure Pharmacokinetics of Meloxicam, Ketoprofen, and
Tolfenamic Acid of Formulations Described in Example 1 in Cattle

[0084] The post-dosing plasma concentration of the active components of
the formulations described in Example 1 was assessed in a research study

[0085] 3 pairs of cattle were randomly assigned to transdermal treatment
with one of the formulations described in Example 1 on Day 0 of the
experiment. One week after transdermal treatment (Day 7 of the
experiment), the cattle were treated with an injectable formulation of
the same active used on Day 0. Injectable products were given in
accordance with label instructions for cattle. Blood samples for
concentration of meloxicam, ketoprofen, or tolfenamic acid were obtained
at 0 (pre-dose) hours, and 1, 2, 4, 6, and 24 hours after dosing. The
doses of the transdermal formulations described in Example 1 were given
at twice the injectable doses on a mg/kg basis.

[0087] Surprisingly, for each active, the plasma concentration following
transdermal dosing was similar to injectable dosing, thus illustrating
the effectiveness of the currently described formulations at driving
these NSAIDs through cattle hide and into the systemic circulation.

Patent applications by Cheyney Meadows, Summit, NJ US

Patent applications by John Gerard Sheehan, Summit, NJ US

Patent applications by Keith Freehauf, Summit, NJ US

Patent applications in class One of the cyclos is a 1,2-thiazine (e.g.,1,2-benzothiazines, etc.)

Patent applications in all subclasses One of the cyclos is a 1,2-thiazine (e.g.,1,2-benzothiazines, etc.)